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Current Research and Scholarly Interests

Chronic pain sufferers are unfortunately limited by poor diagnostic tests and therapies. Our research group is interested in 'imaging pain' by using multimodality molecular imaging techniques to study peripheral nociception and inflammation with the goal of accurately identifying pain generators. We are developing new approaches with positron emission tomography (PET) and magnetic resonance imaging (MRI) (PET/MRI) and are currently in clinical trials.

Clinical Trials

F18PET/CT Versus TC-MDP Scanning to Detect Bone MetsNot Recruiting

The primary objective is to compare the diagnostic performance of 18F- Fluoride PET/CT
scanning to that of conventional bone scanning for detecting cancer that has spread to the
bone (bone metastasis). The intent of the study is to determine whether 18F-Fluoride PET/CT
will lead to improved treatment and patient outcomes.

Stanford is currently not accepting patients for this trial.For more information, please contact Andrei Iagaru, (650) 736 - 2859.

[18F]FTC-146 PET/MRI in Healthy Volunteers and in CRPS and SciaticaRecruiting

Chronic pain can result from injured or inflamed nerves, as happens in people suffering from
sciatica and CRPS. These nerve injuries or regions of nerve irritation are often the cause
of pain in these conditions, but the current diagnostic tools have proven quite limited in
pinpointing these areas. Several studies have implicated involvement of sigma-1 receptors in
the generation and perpetuation of chronic pain conditions, while others are investigating
anti sigma-1 receptor drugs for the treatment of chronic pain. Using [18F]FTC-146, a sigma-1
receptor (S1R) detector and experimental radiotracer, and positron emission
tomography/magnetic resonance imaging (PET/MRI), we hope to learn the best approach to
identifying the site of nerve injury/inflammation (or other tissue injury/inflammation) as
they related to painful conditions, and, therefore, help identify the source of pain
generation. We will characterizing the disease in patients suffering from complex regional
pain syndrome (CRPS) and chronic sciatica, with the overarching goal of optimizing or
developing improved pain treatment regimens.
The broad objectives of this study are:
- To determine the dosimetry of [18F]FTC-146
- To evaluate the safety of [18F]FTC-146 after a single administration
- To evaluate the pharmacokinetics and ability of the radiotracer to reflect S1R
expression in healthy subjects and specific patient subpopulations .
The study is not designed to induce any physiological/pharmacological effect.

Fluorine-18 Fluorodeoxyglucose (F-18 FDG) PET/CT is established as a powerful imaging tool
for cancer detection and monitoring response to therapy. Sodium Fluorine-18 (F-18) was used
in the 1970s for bone scanning and can be used as a skeletal tracer in current PET/CT
scanners. The combined administration of F-18 and F-18 FDG in a single PET/CT scan for
cancer detection was not attempted to date. We hope to learn what is the best approach for
detection of cancer and thus to improve cancer treatment.

Abstract

As chronic pain affects 115 million people and costs $600B annually in the US alone, effective noninvasive nonpharmacological remedies are desirable. The purpose of this study was to determine the efficacy and the generalisability of Noxipoint therapy (NT), a novel electrotherapy characterised by site-specific stimulation, intensity-and-submodality-specific settings and a immobilization period, for chronic neck and shoulder pain. Ninety-seven heavily pretreated severe chronic neck/shoulder pain patients were recruited; 34 and 44 patients were randomly allocated to different treatment arms in two patient-and-assessor-blinded, randomised controlled studies. The participants received NT or conventional physical therapy including transcutaneous electrical nerve stimulation (PT-TENS) for three to six 90-minute sessions. In Study One, NT improved chronic pain (-89.6%, Brief Pain Inventory, p

Abstract

The combined administration of F-NaF and F-FDG in a single PET/CT scan has the potential to improve patient convenience and cancer detection. Here we report the use of this approach for patients with sarcomas.This is a retrospective review of 21 patients (12 men, 9 women; age, 19-66 years) with biopsy-proven sarcomas who had separate F-NaF PET/CT, F-FDG PET/CT, and combined F-NaF/F-FDG PET/CT scans for evaluation of malignancy. Two board-certified nuclear medicine physicians and 1 board-certified musculoskeletal radiologist were randomly assigned to review the scans. Results were analyzed for sensitivity and specificity, using linear regression and receiver operating characteristics.A total of 13 patients had metastatic disease on F-NaF PET/CT, F-FDG PET/CT, and combined F-NaF/F-FDG PET/CT. Skeletal disease was more extensive on the F-NaF PET/CT scan than on the F-FDG PET/CT in 3 patients, whereas in 1 patient, F-FDG PET/CT showed skeletal disease and the F-NaF PET/CT was negative. Extraskeletal lesions were detected on both F-FDG and combined F-NaF/F-FDG PET/CT in 20 patients, with 1 discordant finding in the lung.The combined F-NaF/F-FDG PET/CT scan allows for accurate evaluation of sarcoma patients. Further evaluation of this proposed imaging modality is warranted to identify the most suitable clinical scenarios, including initial treatment strategy and evaluation of response to therapy.

Abstract

Although the applications of adipose tissue-derived cells (ADCs) in regenerative medicine have been investigated, the role of ADCs in fracture healing remains unclear. In this study, we examined the fracture-healing effects and survival of transplanted ADCs using micro-computed tomography (CT) and bioluminescence imaging (BLI).Luciferase-expressing ADCs were suspended in solubilized basement membrane preparation (SBMP) and xenografted on defects in the right femur of nude mice (n=5). SBMP alone was grafted on a defect in the contralateral femur. Serial in vivo micro-CT and BLI were performed for 20 days. Ex vivo BLI images of both femurs were obtained. Differences in the Hounsfield unit (HU), HU(ratio), and luciferase activities were compared using Wilcoxon signed-rank tests and non-parametric longitudinal analyses (p<0.05).In vivo BLI revealed a signal drop on day 2, reconstitution on day 5, and continuous decrement thereafter. Ex vivo BLI revealed residual activity in the ADC-implanted and adjacent areas. No activity was detected in the contralateral femur. The overall increment rate of normalized HUs was higher for ADC-treated femurs than for SBMP-treated femurs. Cell migration to distant injury sites was not detected.Enhanced bone density in the implant area suggests that ADCs have fracture-healing effects.

Abstract

Molecular and cellular imaging of neuropathic pain, utilizing the myriad of receptors and inflammatory mediators involved in nociceptive activity, is a promising approach toward objectively identifying peripheral pain generators. Neuropathic conditions arise from injured and inflamed nerves, which have been shown to elaborate several molecular and cellular elements that give rise to the neuropathic phenotype and can be exploited for imaging purposes. As such, in vivo approaches to image neuropathic pain mechanisms include imaging voltage-gated sodium channels with radiolabeled saxitoxin, calcium signaling with manganese-enhanced magnetic resonance imaging, and inflammatory changes and nerve metabolism with (18)F-fluorodeoxyglucose. Imaging approaches exploiting other mediators of nociceptive activity, such as substance P (neurokinin-1) receptor, sigma-1 receptor, and macrophages, have shown promising early advances in animal models. By combining the sensitivity and specificity of molecular imaging with the high anatomical, spatial and contrast resolution afforded by computed tomography and MRI, radiologists can potentially identify sites of nerve injury or neuroinflammation that are implicated as peripheral pain drivers with greater accuracy and confidence. In addition to guiding therapy, these approaches will aid in new drug designs for analgesia and more individualized treatment options.

Abstract

There are conflicting data describing the effect of mesenchymal stem cells (MSCs) on tumorigenesis. The present study aimed to determine the survival rate and effect of adipose tissue-derived MSCs (ADMSCs) in tumor growth using bioluminescence imaging (BLI) and ultrasound (US) in an osteosarcoma xenograft model. Firefly luciferase-expressing ADMSCs combined with the osteosarcoma cell line UMR-106 in 4 different proportions (5, 10, 15 and 25%, named G1-G4, respectively) were xenografted into the right flanks of nude mice. The same number of UMR-106 cells was inoculated into the contralateral side of each mouse. Serial bioluminescence images were captured over 16 days to monitor the presence of ADMSCs in each group of 5 animals. The tumor volume was measured by ultra-high resolution US, and the tumor volume ratio (AMDSC mixed xenograft/control xenograft) was obtained to evaluate the effect of AMDSCs on tumor growth. Immunohistochemistry was performed to confirm the distribution of residual AMDSCs in the tumor. In G1, G2 and G3, the suppression of tumor growth by AMDSCs was noted in 2/5, 4/5 and 4/5 mice, respectively. However, accelerated tumor growth was noted in G4, which had the highest proportion of ADMSCs. The tumor volume ratio was significantly lower in G2 and G3 compared to G4, by Mann-Whitney U test (P=0.0159). Bioluminescence images demonstrated a serial decrement of the reporter gene for ADMSCs in the tumor mass without evidence of proliferation. Immunohistochemistry staining revealed minimal residual ADMSCs in the tumor periphery. Taken together, our data revealed that direct inoculation of ADMSCs into a tumor xenograft caused the death of the majority of ADMSCs in the tumor mass. Furthermore, relatively low proportions of ADMSCs suppressed the growth of osteosarcoma, while higher proportions showed a tumor-promoting effect.

Abstract

To investigate the prevalence of repetitive strain injury (RSI) among breast-imaging radiologists, the factors associated with such symptoms, and strategies to reduce injury.In 2012, an anonymous survey regarding RSI and work habits was administered to 2,618 physician members of the Society of Breast Imaging via e-mail. Analysis of 727 (27.8%) de-identified responses was completed using STATA 12.1. Pain levels before and after implementation of digital imaging were compared with the Wilcoxon signed-rank test. The associations between RSI symptoms and work habits were assessed with logistic regression and test for trend.In the survey 438 of 727 (60.2%) respondents reported RSI symptoms, and 242 of 727 (33.3%) reported prior diagnosis/treatment. Results showed a statistically significant trend for the odds of RSI symptoms to increase with decreasing age (P = .0004) or increasing number of daily hours spent working (P = .0006), especially in an awkward position (P < .0001). Respondents recalled a significant increase in pain level after implementation of PACS, and a decrease in pain after ergonomic training or initiating use of an ergonomic mouse, adjustable chair, or adjustable table (P < .001, all comparisons). Only 17.7% (129 of 727) used an ergonomic mouse and 13.3% (97 of 727) had attended ergonomic training. Those with RSI symptoms or prior diagnosis of a Repetitive Strain Syndrome (RSS) were more likely to desire future ergonomic training compared with those without symptoms or injury (odds ratio 5.36, P < .001; odds ratio 2.63, P = .001, respectively).RSI is highly prevalent among breast-imaging radiologists nationwide and may worsen after implementation of PACS or with longer work hours. Ergonomic training and ergonomic devices may diminish or prevent painful RSI among radiologists.

Abstract

The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

Abstract

The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

Abstract

Both chronic and neuropathic pain conditions are associated with increased expression of certain voltage-gated sodium ion channel (NaV) isoforms in peripheral sensory neurons. A method for noninvasive imaging of these channels could represent a powerful tool for investigating aberrant expression of NaV and its role in pain pathogenesis. Herein, we describe the synthesis and evaluation of a positron emission tomography (PET) radiotracer targeting NaVs, the design of which is based on the potent, NaV-selective inhibitor saxitoxin. Both autoradiography analysis of sciatic nerves excised from injured rats as well as whole animal PET-MR imaging demonstrate that a systemically administered [(18)F]-labeled saxitoxin derivative concentrates at the site of nerve injury, consistent with upregulated sodium channel expression following axotomy. This type of PET agent has potential use for serial monitoring of channel expression levels at injured nerves throughout wound healing and/or following drug treatment. Such information may be correlated with pain behavioral analyses to help shed light on the complex molecular processes that underlie pain sensation.

Abstract

OBJECTIVE. A review of the innovative role molecular imaging plays in musculoskeletal radiology is provided. Musculoskeletal molecular imaging is under development in four key areas: imaging the activity of osteoblasts and osteoclasts, imaging of molecular and cellular biomarkers of arthritic joint destruction, cellular imaging of osteomyelitis, and imaging generators of musculoskeletal pain. CONCLUSION. Together, these applications suggest that next-generation musculoskeletal radiology will facilitate quantitative visualization of molecular and cellular biomarkers, an advancement that appeared futuristic just a decade ago.

Abstract

Natural language processing (NLP) techniques to extract data from unstructured text into formal computer representations are valuable for creating robust, scalable methods to mine data in medical documents and radiology reports. As voice recognition (VR) becomes more prevalent in radiology practice, there is opportunity for implementing NLP in real time for decision-support applications such as context-aware information retrieval. For example, as the radiologist dictates a report, an NLP algorithm can extract concepts from the text and retrieve relevant classification or diagnosis criteria or calculate disease probability. NLP can work in parallel with VR to potentially facilitate evidence-based reporting (for example, automatically retrieving the Bosniak classification when the radiologist describes a kidney cyst). For these reasons, we developed and validated an NLP system which extracts fracture and anatomy concepts from unstructured text and retrieves relevant bone fracture knowledge. We implement our NLP in an HTML5 web application to demonstrate a proof-of-concept feedback NLP system which retrieves bone fracture knowledge in real time.

Abstract

Manganese-enhanced magnetic resonance imaging (MRI) is a surrogate method to measure calcium content in nervous system since manganese physiologically follows calcium. Manganese is detectable in MRI and therefore visualizes structures and cell populations that actively regulate calcium. Since calcium is actively recruited for the transmission of action potentials, our purpose is to validate manganese-enhanced MRI for detection of changes in lumbar nerves related to nociception. A neuropathic pain model was created by chronic constrictive injury of the left sciatic nerve of Sprague-Dawley rats. Behavioral measurements, using von Frey's tests, confirmed the presence of significant allodynia in the left hind limb of animals in the injured group. T1-weighted fast spin echo images were obtained of the lumbar cord and plexus of animals with injured left sciatic nerve and uninjured animals (control) scanned in a 7 Tesla magnet after intraperitoneal manganese chloride administration four weeks after surgery. Lumbar nerve roots and sciatic nerves in the injured group show increased normalized manganese-enhanced MRI signal, representing manganese enhancement, compared to the control group. In conclusion, animals with neuropathic pain in the left hind limb show increased manganese uptake in not only the injured sciatic nerve but also in the contralateral uninjured sciatic nerve on manganese-enhanced MRI in vivo. Although poorly understood, this finding corroborates ex vivo finding of bilateral nociceptive-related molecular changes in the nervous system of unilateral pain models.

Abstract

Understanding how relevant cell types respond to wear particles will reveal new avenues for treating osteolysis following joint replacements. In this study, we investigate the effects of ultrahigh molecular weight polyethylene (UHMWPE) particles on preosteoblast migration and function. We infused UHMWPE particles or saline into the left femur of mice and injected luciferase-expressing preosteoblasts (MC3T3 cells) into each left ventricle. Bioluminescence imaging (BLI) confirmed systemic administration of MC3T3 cells. BLI throughout the 28-day experiment showed greater MC3T3 migration to the site of particle infusion than to the site of saline infusion, with significant differences on days 0, 4, and 6 (p?0.055). Immunostaining revealed a greater number of osteoblasts and osteoclasts in the particle-infused femora, indicating greater bone turnover. The bone mineralization of the particle-infused femora increased significantly when compared to saline-infused femora (an increase of 146.4±27.9 vs. 12.8±8.7?mg/mL, p=0.008). These results show that infused preosteoblasts can migrate to the site of wear particles. Additionally, as the migrated cells were associated with increased bone mineralization in spite of the presence of particles, increasing osteoblast recruitment is a potential strategy for combating bone loss due to increased osteoclast/macrophage number and decreased osteoblast function.

Abstract

Using magnetic resonance imaging (MRI), evaluate the correlation of acromion angulation with thickening of the coracoacromial ligament (CAL) and narrowing of the subacromial space resulting in impingement upon the rotator cuff tendons.Eighty-nine shoulder MRI studies performed on a 3T scanner were retrospectively analyzed by two blinded independent reviewers. Measurements of the acromion angle (delta angle), CAL thickness and distance between the CAL and humeral head were obtained. The data were categorized into two groups, delta angle less that and greater than 7.5°. The presence or absence of full thickness (FT) or near full thickness (NFT) rotator cuff tears was noted.In group 1, the acromion angle varied from -6.8 to 6.8° (1.7±3.5°) with a CAL thickness of 0.91±0.20 mm and a subacromial distance of 6.47±0.88 mm. Group 2 acromion angle varied from 7.6° to 46.8° (18.0°±8.1°) with a CAL of 1.77±0.51 mm and a subacromial distance of 4.52±0.82 mm. The difference in CAL thickness and subacromial distance were significantly different between the two groups (P

Abstract

To evaluate the potential and correlation between near-infrared fluorescence (NIRF) imaging using cyanine 5.5 conjugated with hydrophobically modified glycol chitosan nanoparticles (HGC-Cy5.5) and (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) imaging of collagen-induced arthritis (CIA).We used 10 CIA and 3 normal mice. Nine days after the injecting collagen twice, microPET imaging was performed 40 minutes after the intravenous injection of 9.3 MBq (18)F-FDG in 200 µL PBS. One day later, NIRF imaging was performed two hours after the intravenous injection of HGC-cy5.5 (5 mg/kg). We assessed the correlation between these two modalities in the knees and ankles of CIA mice.The mean standardized uptake values of (18)F-FDG for knees and ankles were 1.68 ± 0.76 and 0.79 ± 0.71, respectively, for CIA mice; and 0.57 ± 0.17 and 0.54 ± 0.20 respectively for control mice. From the NIRF images, the total photon counts per 30 mm(2) for knees and ankles were 2.32 ± 1.54 × 10(5) and 2.75 ± 1.51 × 10(5), respectively, for CIA mice, and 1.22 ± 0.27 × 10(5) and 0.88 ± 0.24 × 10(5), respectively, for control mice. These two modalities showed a moderate correlation for knees (r = 0.604, p = 0.005) and ankles (r = 0.464, p = 0.039). Moreover, both HGC-Cy5.5 (p = 0.002) and (18)F-FDG-PET (p = 0.005) imaging also showed statistically significant differences between CIA and normal mice.NIRF imaging using HGC-Cy5.5 was moderately correlated with (18)F-FDG-PET imaging in the CIA model. As such, HGC-Cy5.5 imaging can be used for the early detection of rheumatoid arthritis.

Abstract

Minocycline has proven anti-nociceptive effects, but the mechanism by which minocycline delays the development of allodynia and hyperalgesia after peripheral nerve injury remains unclear. Inflammatory cells, in particular macrophages, are critical components of the response to nerve injury. Using ultrasmall superparamagnetic iron oxide-magnetic resonance imaging (USPIO-MRI) to monitor macrophage trafficking, the purpose of this project is to determine whether minocycline modulates macrophage trafficking to the site of nerve injury in vivo and, in turn, results in altered pain thresholds.Animal experiments were approved by Stanford IACUC. A model of neuropathic pain was created using the Spared Nerve Injury (SNI) model that involves ligation of the left sciatic nerve in the left thigh of adult Sprague-Dawley rats. Animals with SNI and uninjured animals were then injected with/without USPIOs (300??mol/kg i.v.) and with/without minocycline (50?mg/kg i.p.). Bilateral sciatic nerves were scanned with a volume coil in a 7?T magnet 7?days after USPIO administration. Fluid-sensitive MR images were obtained, and ROIs were placed on bilateral sciatic nerves to quantify signal intensity. Pain behavior modulation by minocycline was measured using the Von Frey filament test. Sciatic nerves were ultimately harvested at day 7, fixed in 10% buffered formalin and stained for the presence of iron oxide-laden macrophages. Behavioral measurements confirmed the presence of allodynia in the neuropathic pain model while the uninjured and minocycline-treated injured group had significantly higher paw withdrawal thresholds (p?0.011). Decreased MR signal is observed in the SNI group that received USPIOs (3.3+/-0.5%) compared to the minocycline-treated SNI group that received USPIOs (15.2+/-4.5%) and minocycline-treated group that did not receive USPIOs (41.2+/-2.3%) (p?0.04). Histology of harvested sciatic nerve specimens confirmed the presence USPIOs at the nerve injury site in the SNI group without minocycline treatment.Animals with neuropathic pain in the left hindpaw show increased trafficking of USPIO-laden macrophages to the site of sciatic nerve injury. Minocycline to retards the migration of macrophages to the nerve injury site, which may partly explain its anti-nociceptive effects. USPIO-MRI is an effective in vivo imaging tool to study the role of macrophages in the development of neuropathic pain.

Abstract

Particle-associated periprosthetic osteolysis remains a major issue in joint replacement. Ongoing bone loss resulting from wear particle-induced inflammation is accompanied by continued attempts at bone repair. Previously we showed that mesenchymal stem cells (MSCs) are recruited systemically to bone exposed to continuous infusion of ultra high molecular weight polyethylene (UHMWPE) particles. The chemokine-receptor axis that mediates this process is unknown. We tested two hypotheses: (1) the CCR1 receptor mediates the systemic recruitment of MSCs to UHMWPE particles and (2) recruited MSCs are able to differentiate into functional mature osteoblasts and decrease particle-associated bone loss. Nude mice were allocated randomly to four groups. UHMWPE particles were continuously infused into the femoral shaft using a micro-pump. Genetically modified murine wild type reporter MSCs were injected systemically via the left ventricle. Non-invasive imaging was used to assay MSC migration and bone mineral density. Bioluminescence and immunohistochemistry confirmed the chemotaxis of reporter cells and their differentiation into mature osteoblasts in the presence of infused particles. Injection of a CCR1 antagonist decreased reporter cell recruitment to the UHMWPE particle infusion site and increased osteolysis. CCR1 appears to be a critical receptor for chemotaxis of MSCs in the presence of UHMWPE particles. Interference with CCR1 exacerbates particle-induced bone loss.

Abstract

Although iliac crest autologous bone graft remains the gold standard for treatment of bone defects, delayed- and nonunions, and arthrodeses, several alternative strategies have been attempted, including the use of mesenchymal stem cells. Whether cells from the osteoblast lineage demonstrate systemic recruitment to an acute bone defect or fracture, and whether these cells directly participate in bone healing is controversial. This study tests two hypotheses: (1) that exogenous murine MC3T3-E1 osteoprogenitor cells with a high propensity for osteoblast differentiation are able to systemically migrate to a bone defect and (2) that the migrated MC3T3-E1 cells enhance bone healing. Two groups of nude mice were used; a bone defect was drilled in the left femoral shaft in both groups. MC3T3-E1 were used as reporter cells and injected in the left ventricle of the heart, to avoid sequestration in the lungs. Injection of saline served as a control. We used bioluminescence and microCT to assay cell recruitment and bone mineral density (BMD). Immunohistochemical staining was used to confirm the migration of reporter cells. MC3T3-E1 cells were found to systemically migrate to the bone defect. Further, BMD at the defect was significantly increased when cells were injected. Systemic cell therapy using osteoprogenitor cells may be a potential strategy to enhance bone healing.

Abstract

The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T(1)-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D(3) by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T(1)-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity.

Abstract

The biological mechanisms leading to periprosthetic osteolysis involve both chemokines and the monocyte/macrophage cell lineage. Whether MCP-1 plays a major role in macrophage recruitment in the presence of wear particles is unknown. We tested two hypotheses: (1) that exogenous local delivery of MCP-1 induces systematic macrophage recruitment and (2) that blockade of the MCP-1 ligand-receptor axis decreases macrophage recruitment and osteolysis in the presence of ultra high molecular weight polyethylene (UHMWPE) particles. Six groups of nude mice were used. We used non-invasive imaging to assay macrophage recruitment and osteolysis. A murine macrophage cell line and primary wild type and CCR2 knockout murine macrophages were used as the reporter cells. Particles were infused into the femoral canal. Bioluminescence and immunohistochemical staining were used to confirm the migration of reporter cells. Locally infused MCP-1 induced systemic macrophage trafficking to bone. Injection of MCP-1 receptor antagonist significantly decreased reporter cell recruitment to bone infused with UHMWPE particles and decreased osteolysis. Systemic migration of reporter cells to infused particles was decreased when the reporter cells were deficient in the CCR2 receptor. Interruption of the MCP-1 ligand-receptor axis appears to be a viable strategy to mitigate trafficking of macrophages and osteolysis due to UHMWPE particles.

Abstract

Molecular imaging has undergone an explosive advancement in recent years, due to the tremendous research efforts made to understand and visualize biological processes. Molecular imaging by definition assesses cellular and molecular processes in living subjects, with the targets of following metabolic, genomic, and proteomic events. Furthermore, reporter gene imaging plays a central role in this field. Many different approaches have been used to visualize genetic events in living subjects, such as, optical, radionuclide, and magnetic resonance imaging. Compared with the other techniques, magnetic resonance (MR)-based reporter gene imaging has not occupied center stage, despite its superior three-dimensional depictions of anatomical details. In this article, the authors review the principles and applications of various types of MR reporter gene imaging technologies and discuss their advantages and disadvantages.

Abstract

Retrospective review.To (1) propose a standard method to quantitate 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake in the spinal cord and (2) use this methodology to retrospectively characterize the pattern of uptake within the entire spinal cord using whole-body positron emission tomography/computed tomography (PET/CT) imaging.A physiologic understanding of glucose metabolism within the spinal cord may provide insight regarding infectious, inflammatory, vascular, and neoplastic spinal cord diseases.Institutional review board approval was obtained. A total of 131 consecutive whole-body PET/CT studies from July to August 2004 were reviewed, and using exclusionary criteria of: (1) severe spinal arthropathy or curvature, (2) motion artifact, (3) canal hardware, (4) spinal tumor, and (5) marrow hyperplasia, 92 studies of neurologically intact patients (49 men and 43 women) were selected for a retrospective review of spinal cord 18F-FDG activity. The transaxial CT was used to define the canal and circular regions of interests were placed within the canal at the level of the vertebral body midpoint from C1 to L3. Region of interest total count, area, and maximum standardized uptake value (SUVmax) were recorded. Measurements at L5 served as an internal control. For comparative analysis, the cord-to-background (CTB) ratio was defined as spinal cord SUVmax to L5 SUVmax.Mean CTB decreased along each spinal level from cranial to caudal (P < 0.001). Significant relative increases were observed at the T11-T12 vertebral body levels (P < 0.001). Although insignificant, a relative increase was observed at C4. No significant interactions of age or sex on CTB were observed.The pattern of 18F-FDG uptake within the spinal cord, observed in patients with non-central nervous system malignancy, may be helpful in understanding glucose physiology of spinal cord diseases and warrants further research.

Abstract

We demonstrated increased (18)F-FDG uptake in injured peripheral nerves in a model of neuropathic pain using small-animal PET/MRI.A neuropathic pain model in rats was created by spared-nerve injury of the left sciatic nerve. Sham-operated rats without nerve injury were used as a control. The presence of pain was confirmed by testing for allodynia. Sequential small-animal (18)F-FDG PET and MRI scans of the thighs were obtained and coregistered. Autoradiography was performed on harvested nerves and muscle.The group with spared-nerve injury showed the development of allodynia in the operated limb (P < 0.001). Increased (18)F-FDG uptake was observed on both PET/MRI (P < 0.001) and autoradiography (P < 0.005) in the operated nerve in this group. (18)F-FDG uptake in the nerves correlated well with allodynia (? = -0.59; P < 0.024).Animals with neuropathic pain show increased (18)F-FDG uptake in the affected nerve. Small-animal PET/MRI can be effectively used to localize (18)F-FDG uptake in peripheral nerves.

Abstract

Aseptic loosening and periprosthetic osteolysis resulting from wear debris are major complications of total joint arthroplasty. Monocyte/macrophages are the key cells related to osteolysis at the bone-implant interface of joint arthroplasties. Whether the monocyte/macrophages found at the implant interface in the presence of polyethylene particles are locally or systemically derived is unknown.We therefore asked (1) whether macrophages associated with polyethylene particle-induced chronic inflammation are recruited locally or systemically and (2) whether the recruited macrophages are associated with enhanced osteolysis locally.Noninvasive in vivo imaging techniques (bioluminescence and microCT) were used to investigate initial macrophage migration systemically from a remote injection site to polyethylene wear particles continuously infused into the femoral canal. We used histologic and immunohistologic staining to confirm localization of migrated macrophages to the polyethylene particle-treated femoral canals and monitor cellular markers of bone remodeling.The values for bioluminescence were increased for animals receiving UHMWPE particles compared with the group in which the carrier saline was infused. At Day 8, the ratio of bioluminescence (operated femur divided by nonoperated contralateral femur of each animal) for the UHMWPE group was 13.95 ± 5.65, whereas the ratio for the saline group was 2.60 ± 1.14. Immunohistologic analysis demonstrated the presence of reporter macrophages in the UHMWPE particle-implanted femora only. MicroCT scans showed the bone mineral density for the group with both UHMWPE particles and macrophage was lower than the control groups.Infusion of clinically relevant polyethylene particles, similar to the human scenario, stimulated systemic migration of remotely injected macrophages and local net bone resorption.

Abstract

Storing and retrieving radiology cases is an important activity for education and clinical research, but this process can be time-consuming. In the process of structuring reports and images into organized teaching files, incidental pathologic conditions not pertinent to the primary teaching point can be omitted, as when a user saves images of an aortic dissection case but disregards the incidental osteoid osteoma. An alternate strategy for identifying teaching cases is text search of reports in radiology information systems (RIS), but retrieved reports are unstructured, teaching-related content is not highlighted, and patient identifying information is not removed. Furthermore, searching unstructured reports requires sophisticated retrieval methods to achieve useful results. An open-source, RadLex(®)-compatible teaching file solution called RADTF, which uses natural language processing (NLP) methods to process radiology reports, was developed to create a searchable teaching resource from the RIS and the picture archiving and communication system (PACS). The NLP system extracts and de-identifies teaching-relevant statements from full reports to generate a stand-alone database, thus converting existing RIS archives into an on-demand source of teaching material. Using RADTF, the authors generated a semantic search-enabled, Web-based radiology archive containing over 700,000 cases with millions of images. RADTF combines a compact representation of the teaching-relevant content in radiology reports and a versatile search engine with the scale of the entire RIS-PACS collection of case material.

Abstract

Macrophages constitute a major part of the cell response to wear particles produced at articulating and nonarticulating interfaces of joint replacements. This foreign body reaction can result in periprosthetic osteolysis and implant loosening. We demonstrate that ultra-high molecular weight polyethylene (UHMWPE) particles induce systemic trafficking of macrophages by noninvasive in vivo imaging and immunohistochemistry. The distal femora of nude mice were injected with 60 mg/mL UHMWPE suspension or saline alone. Reporter RAW264.7 macrophages that stably expressed the bioluminescent reporter gene and the fluorescence reporter gene were injected intravenously. Bioluminescence imaging was performed using an in vivo imaging system immediately after macrophage injection and at 2-day intervals. Compared with the nonoperated contralateral femora, at day 4, 6, and 8, the bioluminescent signal of femora containing UHMWPE suspension increased 1.30 +/- 0.09-, 2.36 +/- 0.92-, and 10.32 +/- 7.61-fold, respectively. The values at same time points for saline-injected control group were 1.08 +/- 0.07-, 1.14 +/- 0.27-, and 1.14 +/- 0.35-fold, respectively. The relative bioluminescence of the UHMWPE group was higher at all postinjection days and significantly greater than the saline group at day 8 (p < 0.05). Histological analysis confirmed the presence of reporter macrophages within the medullary canal of mice with implanted UHMWPE particles. The presence of UHMWPE particles induced enhanced bone remodeling activity. Clinically relevant UHMWPE particles stimulated the systemic recruitment of macrophages during an early time course using the murine femoral implant model. Interference with systemic macrophage trafficking may potentially mitigate UHMWPE particle-induced periprosthetic osteolysis.

Abstract

Transcriptional targeting for cardiac gene therapy is limited by the relatively weak activity of most cardiac-specific promoters. We have developed a bidirectional plasmid vector, which uses a two-step transcriptional amplification (TSTA) strategy to enhance the expression of two optical reporter genes, firefly luciferase (fluc) and Renilla luciferase (hrluc), driven by the cardiac troponin T (cTnT) promoter. The vector was characterized in vitro and in living mice using luminometry and bioluminescence imaging to assess its ability to mediate strong, correlated reporter gene expression in a cardiac cell line and the myocardium, while minimizing expression in non-cardiac cell lines and the liver. In vitro, the TSTA system significantly enhanced cTnT-mediated reporter gene expression with moderate preservation of cardiac specificity. After intramyocardial and hydrodynamic tail vein delivery of an hrluc-enhanced variant of the vector, long-term fluc expression was observed in the heart, but not in the liver. In both the cardiac cell line and the myocardium, fluc expression correlated well with hrluc expression. These results show the vector's ability to effectively amplify and couple transgene expression in a cardiac-specific manner. Further replacement of either reporter gene with a therapeutic gene should allow non-invasive imaging of targeted gene therapy in living subjects.

Abstract

A key challenge in developing nanoplatform-based molecular imaging is to achieve an optimal pharmacokinetic profile to allow sufficient targeting and to avoid rapid clearance by the reticuloendothelial system (RES). In the present study, iron oxide nanoparticles (IONPs) were coated with a PEGylated amphiphilic triblock copolymer, making them water soluble and function-extendable. These particles were then conjugated with a near-infrared fluorescent (NIRF) dye IRDye800 and cyclic Arginine-Glycine-Aspartic acid (RGD) containing peptide c(RGDyK) for integrin alpha(v)beta(3) targeting. In vitro binding assays confirmed the integrin-specific association between the RGD-particle adducts and U87MG glioblastoma cells. Successful tumor homing in vivo was perceived in a subcutaneous U87MG glioblastoma xenograft model by both magnetic resonance imaging (MRI) and NIRF imaging. Ex vivo histopathological studies also revealed low particle accumulation in the liver, which was attributed to their compact hydrodynamic size and PEGylated coating. In conclusion, we have developed a novel RGD-IONP conjugate with excellent tumor integrin targeting efficiency and specificity as well as limited RES uptake for molecular MRI.

Abstract

The use of regulated gene expression systems is important for successful gene therapy applications. In this study, ligand-induced structural change in the estrogen receptor (ER) was used to develop a novel ER intramolecular folding-based transcriptional activation system. The system was studied using ER-variants of different lengths, flanked on either side by the GAL4-DNA-binding domain and the VP16-transactivation domain (GAL4(DBD)-ER-VP16). The ER ligands of different types showed efficient ligand-regulated transactivation. We also characterized a bidirectional transactivation system based on the ER and demonstrated its utility in titrating both reporter and therapeutic gene expression. The ligand-regulated transactivation system developed by using a mutant form of the ER (G521T, lacking affinity for the endogenous ligand 17beta-estradiol, whereas maintaining affinity for other ligands) showed efficient activation by the ligand raloxifene in living mice without significant interference from the circulating endogenous ligand. The ligand-regulated transactivation system was used to test the therapeutic efficiency of the tumor suppressor protein p53 in HepG2 (p53(+/+)) and SKBr3 (p53(-/-)/mutant-p53(+/+)) cells in culture and tumor xenografts in living mice. The multifunctional capabilities of this system should be useful for gene therapy applications, to study ER biology, to evaluate gene regulation, ER ligand screening, and ER ligand biocharacterization in cells and living animals.

Abstract

Adult stem cells are promising therapeutic reagents for skeletal regeneration. We hope to validate by molecular imaging technologies the in vivo life cycle of adipose-derived multipotent cells (ADMCs) in an animal model of skeletal injury. Primary ADMCs were lentivirally transfected with a fusion reporter gene and injected intravenously into mice with bone injury or sham operation. Bioluminescence imaging (BLI), [(18)F]FHBG (9-(fluoro-hydroxy-methyl-butyl-guanine)-micro-PET, [(18)F]Fluoride ion micro-PET and micro-CT were performed to monitor stem cells and their effect. Bioluminescence microscopy and immunohistochemistry were done for histological confirmation. BLI showed ADMC's traffic from the lungs then to the injury site. BLI microscopy and immunohistochemistry confirmed the ADMCs in the bone defect. Micro-CT measurements showed increased bone healing in the cell-injected group compared to the noninjected group at postoperative day 7 (p < 0.05). Systemically administered ADMC's traffic to the site of skeletal injury and facilitate bone healing, as demonstrated by molecular and small animal imaging. Molecular imaging technologies can validate the usage of adult adipose tissue-derived multipotent cells to promote fracture healing. Imaging can in the future help establish therapeutic strategies including dosage and administration route.

Abstract

Erdheim-Chester disease is an infiltrative form of histiocytosis characterized by replacement of normal tissues by lipid-laden histiocytes. The disease typically infiltrates the medullary portion of the diaphysis and metaphysis of long bones, producing a characteristic radiological pattern dominated by bone sclerosis. It usually affects adults of 40 years of age with a clinical spectrum ranging from an asymptomatic focal bone lesion to multisystemic disease. This case report documents unique imaging and pathologic findings of Erdheim-Chester disease using close postmortem pathologic-imaging correlation.

Abstract

Macrophages play an important role in the biological response to wear particles, which can result in periprosthetic osteolysis and implant loosening. In this study, we demonstrate that polymer particles induce systemic trafficking of macrophages by non-invasive in vivo imaging and immunohistochemistry. The distal femora of nude mice were injected with 10% (w/v) Simplex bone cement (BC) suspensions or saline (PBS). Reporter RAW264.7 macrophages which stably expressed the bioluminescent reporter gene fluc, and the fluorescence reporter gene gfp, were injected intravenously. Bioluminescence imaging was performed immediately and periodically at 2-day intervals until day 14. Compared to the non-operated contralateral femora, the bioluminescent signal of femora injected with BC suspension increased 4.7+/-1.6 and 7.8+/-2.9-fold at day 6 and 8, respectively. The same values for PBS group were 1.2+/-0.2 and 1.4+/-0.5, respectively. The increase of bioluminescence of the BC group was significantly greater than the PBS group at day 8 (p<0.05) and day 6 (p<0.1). Histological study confirmed the presence of reporter macrophages within the medullary canal of mice that received cement particles. Modulation of the signaling mechanisms that regulate systemic macrophage trafficking may provide a new strategy for mitigating the chronic inflammatory response and osteolysis associated with wear debris.

Abstract

The purpose of this study is to compare the local microfracture effects of antegrade versus retrograde drilling of the tibial tunnel in ACL reconstruction. Arthroscopic ACL excision was performed on eight matched cadaveric knees. Arthroscopic guided tibial tunnel reaming was performed in either an antegrade (four) or retrograde (four) direction. A 3 x 3 cm section of proximal tibial surrounding the tibial aperture was removed with open dissection, and each section underwent micro-computed tomography analysis. Three musculoskeletal radiologists graded the specimens for bone aperture disruption and discrete fracture lines. Tibial aperture irregularity was seen in all four of the antegrade specimens (mean, Grade 1.5), and in none of the retrograde specimens. Discrete fracture lines were present in all four antegrade specimens (mean 10.13 mm depth; 8.95 mm length). No fracture lines were seen in the retrograde group. Retrograde drilling of the tibial tunnel in ACL reconstruction results in less microfracture trauma to the surrounding aperture bone. The use of retrograde drilling in ACL reconstruction may decrease synovialization of the graft-tissue interface when compared to antegrade drilling.

Abstract

With the use of a commonly utilized animal model of rheumatoid arthritis, the central goal of this work was to determine how well the small-animal imaging tools, small-animal MRI (microMRI) and small-animal X-ray computed tomography (microCT), can detect very early histological changes that occur immediately after induction of the disease. Arthritis was induced in rats by injecting complete Freund's adjuvant into the tail. Right hind paws of living rats were evaluated with 4.7 T microMRI with T1-weighted spin echo and inversion recovery sequences. Paw specimens were also evaluated with microCT and by histological examination (n = 29). MicroMR images were scored for the presence of joint effusion, soft tissue swelling, bone marrow changes, and bone erosions. MicroCT measured bone mineral density (BMD). Histology scores were obtained from representative slides from the same rats. The correlation between BMD, MRI and histology was analyzed using linear regression analysis and analysis of covariance. MRI abnormalities were detected on day 5 after induction as joint effusion and soft tissue swelling, followed by bone marrow changes on day 6 and bone erosion on day 8. BMD measured by microCT decreased, the decrease becoming significant on day 7 (P < 0.019). Soft tissue swelling, joint effusion, and bone erosion scores on microMRI correlated with histology (r2 approximately 0.7). Bone marrow changes were seen more clearly with microMRI than by histological examination. Bone loss could be detected earlier by microCT than on histological sections. In conclusion, microMRI and microCT can be used to evaluate early disease changes within 1 week of induction in the adjuvant-induced arthritis model, and have the ability to detect certain manifestations of disease earlier than histological analysis. The use of small-animal imaging techniques potentially allows earlier diagnosis, improved subject stratification, earlier drug implementation, and therefore improved drug trials in animal models of rheumatoid arthritis.

Abstract

Imaging abnormalities around the lesser trochanter are occasionally found in long-distance runners, yet little research has been conducted concerning this area of the hip. In addition, the relation between iliopsoas insertional abnormalities at the lesser trochanter and femoral neck stress injuries has not been examined, to our knowledge. We report MRI findings at the lesser trochanter in nine long-distance runners with hip or groin pain and a consistent constellation of the following findings: abnormalities associated with the iliopsoas tendon and its insertion, including marrow edema at the lesser trochanter; periostitis around the lesser trochanter; and bone marrow edema in the femoral neck. One case involved temporal progression to a cortical fracture.Long-distance runners with hip or groin pain and abnormal MRI findings involving the insertion of the iliopsoas tendon and marrow edema in the lesser trochanter may be at risk of stress injuries at the femoral neck.

Abstract

The murine femoral intramedullary injection model is frequently used to examine the in vivo effects of biomaterials or cancer cells. The surgical technique includes a knee arthrotomy with patellar dislocation for intramedullary access. This study examined a less invasive surgical approach of direct injection of particles via the transpatellar tendon without patellar dislocation. By using polymethylmethacrylate injection and microCT scan, we found that, compared with the traditional technique, this new approach was more reproducible, less time consuming, and achieved identical volumes of intramedullary injections. Animal morbidity and the biomechanics of the joints were also improved as a result of the simplified procedure. Furthermore, our study suggested that an intramedullary volume in excess of 10 microL can lead to major vascular filling and so should be avoided.

Abstract

The purpose of this study was to synthesize biocompatible polyvinylpyrrolidone (PVP)-coated iron oxide (PVP-IO) nanoparticles and to evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The PVP-IO nanoparticles were synthesized by a thermal decomposition method and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and a superconducting quantum interface device (SQUID). The core size of the particles is about 8-10 nm and the overall size is around 20-30 nm. The measured r(2) (reciprocal of T(2) relaxation time) and r2? (reciprocal of T2? relaxation time) are 141.2 and 338.1 (s mM)(-1), respectively. The particles are highly soluble and stable in various buffers and in serum. The macrophage uptake of PVP-IO is comparable to that of Feridex as measured by a Prussian blue iron stain and phantom study. The signal intensity of a rabbit liver was effectively reduced after intravenous administration of PVP-IO. Therefore PVP-IO nanoparticles are potentially useful for T(2)-weighted MR imaging.

Abstract

Chronic musculoskeletal diseases such as arthritis, malignancy, and chronic injury and/or inflammation, all of which may produce chronic musculoskeletal pain, often pose challenges for current clinical imaging methods. The ability to distinguish an acute flare from chronic changes in rheumatoid arthritis, to survey early articular cartilage breakdown, to distinguish sarcomatous recurrence from posttherapeutic inflammation, and to directly identify generators of chronic pain are a few examples of current diagnostic limitations. There is hope that a growing field known as molecular imaging will provide solutions to these diagnostic puzzles. These techniques aim to depict, noninvasively, specific abnormal cellular, molecular, and physiologic events associated with these and other diseases. For example, the presence and mobilization of specific cell populations can be monitored with molecular imaging. Cellular metabolism, stress, and apoptosis can also be followed. Furthermore, disease-specific molecules can be targeted, and particular gene-related events can be assayed in living subjects. Relatively recent molecular and cellular imaging protocols confirm important advances in imaging technology, engineering, chemistry, molecular biology, and genetics that have coalesced into a multidisciplinary and multimodality effort. Molecular probes are currently being developed not only for radionuclide-based techniques but also for magnetic resonance (MR) imaging, MR spectroscopy, ultrasonography, and the emerging field of optical imaging. Furthermore, molecular imaging is facilitating the development of molecular therapies and gene therapy, because molecular imaging makes it possible to noninvasively track and monitor targeted molecular therapies. Implementation of molecular imaging procedures will be essential to a clinical imaging practice. With this in mind, the goal of the following discussion is to promote a better understanding of how such procedures may help address specific musculoskeletal issues, both now and in the years ahead.

Abstract

We describe a patient with a history of recurrent squamous cell carcinoma of the tongue and abnormal FDG uptake in the left arm during a re-staging FDG PET/CT. After revision of the patient's clinical history, tests and physical exam, the abnormal FDG uptake was found to correspond to an extensive aseptic deep venous thrombosis of the upper extremity.

Abstract

Our goal was to noninvasively measure chemotherapy-induced changes in the expression of critical tumor growth genes. To achieve this goal, we used radionuclide and optical methods to measure changes in human telomerase reverse transcriptase (hTERT) gene expression in tumor cells before and after 5-fluorouracil treatment.A fusion reporter construct, containing humanized Renilla luciferase (hrl, for bioluminescent imaging), monomeric red fluorescence protein 1 (mrfp1, for fluorescent imaging), and a truncated thymidine kinase (ttk, for imaging of radiolabeled acycloguanosines), was placed under the control of hTERT promoter fragments. These constructs were introduced into tumor cell lines with and without hTERT expression. Transfected cells were treated with 5-fluorouracil, a chemotherapeutic that decreases hTERT gene expression, and treatment-induced changes in hTERT promoter activity were imaged.When the fusion construct is introduced into cell lines that express hTERT, all 3 reporter systems are highly expressed and hTERT promoter activity can be visualized. Cell lines lacking hTERT transcription show no significant reporter expression. Decreases in hTERT gene expression caused by 5-fluorouracil treatment could be visualized in living 293T cells by both fluorescent microscopy and bioluminescent imaging.hTERT promoter activity can be monitored by 1 radionuclide and 2 optical reporter systems using a single reporter construct. This in vitro study provides evidence that our multimodality reporter construct can be used to study the expression of a critical tumor growth gene in living subjects.

Abstract

Erdheim-Chester disease (ECD) is a rare form of histiocytosis of unknown origin characterized by tissue infiltration by lipid-laden histiocytes. Typically, the diaphyseal and metaphyseal portions of the tubular bones are affected, leading to a characteristic radiographic pattern of bone sclerosis. Orbital involvement is not infrequent and is manifested by exophthalmos and periorbital xanthomatous lesions, with associated visual problems. This case report documents imaging and pathologic findings in a patient with ECD with extensive orbital involvement.

Abstract

Mitochondrial membrane potential (DeltaPsim)-dependent enhanced uptake of phosphonium salts, including (3)H-tetraphenylphosphonium ((3)H-TPP), in tumor cells, suggests the potential use of phosphonium salts as tracers for tumor imaging. In this study, we characterize the tumor accumulation of (3)H-TPP and compare it with (18)F-FDG in cell culture and in xenograft, metastatic, and inflammation models in living animals.(3)H-TPP and (3)H-FDG accumulation was compared in cell culture with a variety of cell lines in different glucose concentrations. Normal biodistribution and tumor uptake were assessed using nude mice with or without subcutaneous xenograft tumors (C6). To compare the accumulation of (3)H-TPP and (18)F-FDG in a metastatic tumor, severe combined immunodeficiency mice were tail-vein injected with human melanoma cell lines (A375-FL). To characterize the accumulation of (3)H-TPP and (18)F-FDG in inflammation, an inflammatory reaction was induced by subcutaneous injection of Complete Freund's Adjuvant in the left hind paw of Sprague-Dawley rat.The DeltaPsim data from a separate study and the current (3)H-TPP uptake data showed good correlation (r(2) = 0.82, P < 0.05). (3)H-TPP accumulation was significantly greater than that of (3)H-FDG for glucose >/=100 mg/dL. The biodistribution study of (3)H-TPP showed low uptake in most tissues but high accumulation in the heart and kidneys. (3)H-TPP accumulation in xenograft or metastatic tumors was comparable with that of (18)F-FDG, whereas (3)H-TPP accumulation in inflammatory tissues was markedly lower than that of (18)F-FDG.The sensitive tumor accumulation of (3)H-TPP with less propensity for inflammatory regions warrants further investigation of radiolabeled phosphonium analogs for tumor imaging in living subjects.

Abstract

Chronic musculoskeletal diseases such as arthritis, malignancy, chronic injury/ inflammation, and chronic musculoskeletal pain often pose challenges for current clinical imaging modalities. There is hope that a growing field, referred to as "molecular imaging," will shed new light on these chronic phenomenon as it aims to noninvasively detect special molecular and physiologic effects such as metabolism rate, specific proteins, cell death, and particular gene-related events. Molecular imaging represents recent advances in imaging technology, engineering, chemistry, molecular biology, and genetics that have coalesced into a multidisciplinary and multimodality effort. Molecular probes are currently being developed not only in radionuclide-based techniques but also in magnetic resonance imaging, magnetic resonance spectroscopy, ultrasound, and the emerging field of optical imaging. Furthermore, molecular imagers are fueling the development of novel molecular therapies and gene therapy, as tracking these efforts in living subjects is now possible with molecular imaging protocols.

Abstract

To evaluate the rate of progression of cartilage loss in the knee joint using magnetic resonance imaging (MRI) and to evaluate potential risk factors for more rapid cartilage loss.We evaluated baseline and followup MRIs of the knees in 43 patients (minimum time interval of 1 year, mean 1.8 years, range 52-285 weeks). Cartilage loss was graded in the anterior, central, and posterior regions of the medial and lateral knee compartments. Knee joints were also evaluated for other pathology. Data were analyzed using analysis of variance models.Patients who had sustained meniscal tears showed a higher average rate of progression of cartilage loss (22%) than that seen in those who had intact menisci (14.9%) (P

Abstract

To prospectively assess patient anxiety, understanding of the procedure being performed, perception of pain level, and satisfaction with medication given for a variety of diagnostic and therapeutic vascular and visceral (nonvascular) interventional procedures.The authors interviewed 204 patients before and after they underwent an interventional radiologic procedure. Patients responded to a series of questions by using a visual analog scale. Patients were grouped according to (a) their level of experience with the procedure and (b) the type of procedure performed (diagnostic or therapeutic visceral procedure or diagnostic or therapeutic vascular procedure).Patients who had previous experience with a procedure, whether visceral or vascular, were less anxious, had more understanding, and anticipated less pain than did those who did not have experience with a procedure. Patients who had only local anesthesia for visceral biopsy experienced greater pain than did those who had both local and intravenous anesthesia. Satisfaction scores, however, were similar throughout all groups.Patients have a moderate amount of anxiety about interventional procedures and anticipate some discomfort. Most patients have a high level of satisfaction despite the amount of pain they experience during the procedure. Patients experienced with a procedure tend to have a greater understanding of the procedure and less anxiety.

Abstract

Connexin43 (Cx43) is a member of the family of channel-forming proteins that make up the gap junction and are believed to provide pathways for cell-cell exchange of developmental signals. We have used immunofluorescence and confocal microscopy to characterize the patterns of distribution of Cx43 in postimplantation mouse embryos representing stages of development extending through gastrulation and the major period of organogenesis [through 13.5 days post coitum (dpc)]. We find that Cx43 is expressed early after implantation by the undifferentiated, pluripotent cells of the primitive embryonic ectoderm from which all tissues of the fetus are believed to be derived. As cells become committed to particular developmental pathways, there is a progressive restriction of Cx43 to specific areas and organ systems. The patterns are complex and not limited by germ layer of origin, although there is a clear preference for expression in ectodermal and, to a lesser extent, mesodermal derivatives. Expression in lens, retina, kidney, brain, pineal and pituitary glands is initiated early in organogenesis. In heart, the first clear signal for Cx43 appears in the ventricle at about 10 dpc and is only subsequently detected in the atrium at about 13-13.5 dpc. Particularly intriguing with regard to functional implications is the high level expression observed at sites of inductive interaction; the eye lens and optic cup, the infundibulum and the apical ectodermal ridge of the limb bud.

Abstract

1. The influence of the free radical of diaziquone on inhibition of cell growth in vitro was studied using P388 murine leukaemia cells and a mixture of AZQH2 + AZQ. This mixture generates the AZQ free radical by the disproportionation-comproportionation reaction AZQH2 + AZQ in equilibrium with 2AZQH. 2. Reduced AZQ (AZQH2) was produced electrochemically under anaerobic conditions. This colourless solution was added anaerobically to a solution of AZQ at a 9:1 ratio of AZQH2 to AZQ. The free radical (AZQH) generated was detected by electron spin resonance (ESR) and amounted to about 7% of the concn of AZQH2 + AZQ. The AZQ free radical was stable enough to treat cells in culture. 3. Aerobic suspensions of P388 murine leukaemia cells treated with AZQH experienced a surge of free radicals lasting approx. 30 min at concn near 10 times that of the AZQ free radicals generated by P388 cells. 4. Cell growth inhibition indicates that the concentration of AZQ required to arrest the growth of P388 cells by 50% (IC50) is twice that of the AZQ free radical generating mixture. The mechanism of action of AZQ probably does not exclusively involve AZQ free radicals, but they appear to play an important role.

Abstract

To analyze the mode of action of diaziquone [AZQ] on DNA, we examined the activity of two AZQ analogues and N,N',N"-triethylenethiophosphoramide on three forms [supercoiled (Form I), open circular (Form II), and linear (Form III)] of PM-2 DNA. The AZQ analogues contained chlorine atoms which substituted either the carbethoxyamino groups or the aziridine groups of the parent compound. N,N',N"-triethylenethiophosphoramide is a triaziridine compound containing pentavalent phosphorus instead of a quinone group. We found that only when reduced with sodium borohydride did AZQ change the topology of the three forms of PM-2 DNA by introducing mainly single strand breaks. The AZQ analogue containing only aziridines (RQ2) was active in both its oxidized and its reduced forms, while the analogue containing only the carbethoxyamino groups (RQ14) or N,N',N"-triethylenethiophosphoramide were not active in either form. Under similar experimental conditions, Adriamycin alone altered the electrophoretic mobility of PM-2 DNA, while borohydride reduced Adriamycin did not. By using electron spin resonance spectroscopy, we showed that dihydrodiaziquone (AZQH2) oxidizes to the semiquinone in the presence of oxygen. Although AZQH2 was active against DNA, it was not active against cellular DNA synthesis as measured by [3H]thymidine incorporation into exponentially growing HEp-2 cells. However, AZQ alone prevented [3H]thymidine incorporation into HEp-2 cells. We found that HEp-2 cells have the ability to reduce AZQ to its free radical anion, but AZQH2 does not autoxidize to the free radical in the presence of cells. The reductive ability of HEp-2 cells may be responsible in part for preventing the oxidation of AZQH2 to the free radical. We found that under our conditions (1-h incubations) the aziridines are essential for the activity of aziridinyl quinones against PM-2 DNA and that in the case of AZQ the hydroquinone is also required.